Axitinib Accord

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EK01. Mechanism of action Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and produced tumour growth delay, regression, and inhibition of metastases in many experimental models of cancer. Effect on QTc interval In a randomised, 2-way crossover study, 35 healthy subjects were administered a single oral dose of axitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that axitinib plasma exposures up to two-fold greater than therapeutic levels expected following a 5 mg dose, did not produce clinically-significant QT interval prolongation. Clinical efficacy and safety The safety and efficacy of axitinib were evaluated in a randomised, open-label, multicenter Phase 3 study. Patients (N = 723) with advanced RCC whose disease had progressed on or after treatment with one prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomised (1:1) to receive axitinib (N = 361) or sorafenib (N = 362). The primary endpoint, progression-free survival (PFS), was assessed using a blinded independent central review. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Of the patients enrolled in this study, 389 patients (53.8%) had received one prior sunitinib-based therapy, 251 patients (34.7%) had received one prior cytokine-based therapy (interleukin-2 or interferon-alpha), 59 patients (8.2%) had received one prior bevacizumab-based therapy, and 24 patients (3.3%) had received one prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the axitinib and sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment. In the overall patient population and the two main subgroups (prior sunitinib treatment and prior cytokine treatment), there was a statistically significant advantage for axitinib over sorafenib for the primary endpoint of PFS (see Table 2 and Figures 1, 2 and 3). The magnitude of median PFS effect was different in the subgroups by prior therapy. Two of the subgroups were too small to give reliable results (prior temsirolimus treatment or prior bevacizumab treatment). There were no statistically significant differences between the arms in OS in the overall population or in the subgroups by prior therapy. Table 2. Efficacy results Endpoint / study population Overall ITT axitinib N = 361 sorafenib N = 362 HR (95% CI) p-value Median PFS a,b in months (95% CI) 6.8 (6.4, 8.3) 4.7 (4.6, 6.3) 0.67 (0.56, 0.81) < 0.0001 c Median OS d in months (95% CI) 20.1 (16.7, 23.4) 19.2 (17.5, 22.3) 0.97 (0.80, 1.17) NS ORR b,e % (95% CI) 19.4 (15.4, 23.9) 9.4 (6.6, 12.9) 2.06 f (1.41, 3.00) 0.0001 g Prior sunitinib treatment N = 194 N = 195 Median PFS a,b in months (95% CI) 4.8 (4.5, 6.5) 3.4 (2.8, 4.7) 0.74 (0.58, 0.94) 0.0063 h Median OS d in months (95% CI) 15.2 (12.8, 18.3) 16.5 (13.7, 19.2) 1.00 (0.78, 1.27) NS ORR b,e % (95% CI) 11.3 (7.2, 16.7) 7.7 (4.4, 12.4) 1.48 f (0.79, 2.75) NS Prior cytokine treatment N = 126 N = 125 Median PFS a,b in months (95% CI) 12.0 (10.1, 13.9) 6.6 (6.4, 8.3) 0.52 (0.38, 0.72) < 0.0001 h Median OS d in months (95% CI) 29.4 (24.5, NE) 27.8 (23.1, 34.5) 0.81 (0.56, 1.19) NS ORR b,e % (95% CI) 32.5 (24.5, 41.5) 13.6 (8.1, 20.9) 2.39 f (1.43-3.99) 0.0002 i CI = Confidence interval, HR = Hazard ratio (axitinib/sorafenib); ITT: Intent-to-treat; NE: not estimable; NS: not statistically significant; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival. a Time from randomisation to progression or death due to any cause, whichever occurs first. Cutoff date: 03 June 2011. b Assessed by independent radiology review according to Response Evaluation Criteria in Solid Tumours (RECIST). c One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy. d Cutoff date: 01 November 2011. e Cutoff date: 31 August 2010. f Risk ratio is used for ORR. A risk ratio > 1 indicated a higher likelihood of responding in the axitinib arm; a risk ratio < 1 indicated a higher likelihood of responding in the sorafenib arm. g One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status and prior therapy. h One-sided p-value from a log-rank test of treatment stratified by ECOG performance status. i One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status. Figure 1. Kaplan-Meier curve of progression-free survival by independent assessment for the overall population Figure 2. Kaplan-Meier curve of progression-free survival by independent assessment for the prior sunitinib subgroup Figure 3. Kaplan-Meier curve of progression-free survival by independent assessment for the prior cytokine subgroup Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with the reference product containing axitinib in all subsets of the paediatric population for treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).